An ongoing and pervasive problem in the medical community is treating patients with chronic pain syndromes. It is well recognized today that chronic pain is fundamentally different from acute pain, also referred to as nociceptive pain, which pain results from a mechanical, chemical, metabolic or inflammatory insult.
It has been recognized by some that since the mechanisms and pathways for chronic and acute pain are physiologically different, they require different approaches for treatment. Unfortunately, many in the medical community continue to treat patients suffering from chronic pain syndromes with agents designed to address acute nociceptive pain pathways. Such methods are often fraught with toxicity and dependence issues, and in the end are generally unsatisfactory in ending pain and/or improving quality of life. A new diagnostic paradigm and treatment protocol is therefore needed to address chronic pain.
Central sensitization is a newly recognized diagnostic entity that underlies a broad range of phenotypic syndromes, including various chronic pain and mood disorders. As used herein, central sensitization means an abnormal state of functioning of the neurons and circuitry of the central pain intensity, perception and modulation systems; due to synaptic, chemical, functional and/or structural changes, in which pain is no longer coupled, as acute nociceptive pain is, to particular peripheral stimuli. Instead, the central nervous system (CNS) initiates, maintains and contributes to the generation of pain hypersesensitivity and perception, absent a peripheral stimulus. As used herein, therefore chronic pain and central sensitization represent an overlapping constellation of diagnostic conditions and syndromes.
The present inventors consider the following to be a non-exhaustive listing of conditions associated with (causative or resulting from) central sensitization, each of which is thought to be applicable to humans or other vertebrates.
1. Autonomic neuropathies
2. Chronic back pain
3. Chronic joint pain associated metabolic neuropathy
4. Chronic joint pain associated with inflammation
5. Fibromyalgia
6. Irritable bowel syndrome
7. Migraine
8. Neuropathic pain
9. Osteoarthritis
10. Post Herpetic neuralgia
11. Post surgical pain syndromes
12. Post Traumatic Stress Disorder Pain Syndrome
13. Rheumatoid, arthritic, psoriatic and other chronic arthropathies
14. Spinal nerve compression syndromes associated with neoplasia and/or disc herniation
15 Trigeminal neuralgia
16. Vulvodynia syndrome
Central sensitization is currently thought to be established via a well characterized constellation of cellular changes termed, neuroplasticity. Neuroplasticity consists of the physical remodeling of neuronal and microglial cytoarchitecture; such as changes in synaptic gap junctions, membrane excitability shifts due to ion channel modulation, and gene transcription. Neuroplasticity changes can be bi-directional. In other words, appropriately functioning cells can undergo remodeling that results in a dysfunctional operating state creating the ‘disease states’ of chronic pain and mood disorders. Conversely, these neuroplasticity mediated dysfunctional changes can be reversed with a return to ‘normal’ functioning, which can correspond clinically to a resolution of a ‘disease’ state.
Central sensitization involves, in part, shifts in gene transcription involved in nociception and pain modulation. Huber, et al has clearly shown this phenomenon occurring at specific HCG concentration levels in endometriotic tissue (1). Some of the specific genes identified in this study were genes encoding for G-protein coupled receptor (GPCR) function (2). See:    1. Huber A, Hudelist G, Knofler N, Saleh L, Huber J C, Singer C F. Effect of highly purified human chorionic gonadotropin preparations on the gene expression signature of stromal cells derived from endometriotic lesions: potential mechanisms for the therapeutic effect of human chorionic gonadotropin in vivo. October 2007 Fertility and Sterility Vol. 88, No. Suppl 2.    2. Foukes T, Wood J N. Pain Genes. PLoS Genetics. July 2008 (4)7:e1000086.
These and all other extrinsic materials discussed herein are incorporated by reference in their entirety. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Pain, in general, represents a hyper-excitatory state of neuronal tissue associated with an increase in action potential firing. Action potential generation is the result of increased amplitude and/or frequency of electrical signaling. This is created by the cellular integration of changes in molecular signaling, ion gradients and gene expression resulting in the perception of acute or chronic discomfort.
Pain transmission and modulation through the central nervous system network of neurons and support glial cells (microglia and astrocytes) is largely under the control of a large family of cellular receptors known as G protein-coupled receptors (GPCRs). The function of these complex transmembrane receptors is to transduce extracellular stimuli into intracellular signaling including gene transcription. GPCRs modulate and/or mediate virtually all physiologic processes in eukaryotic organisms, including acute and chronic pain. An estimated 90% of all known GPCRs are expressed in the central nervous system. 80% of the currently proposed GPCR families have a known role in modulation of pain. Similarly, most of the identified genes associated with pain modulation are GPCR related genes. Stone L S, Molliver D C. In search of analgesia: Emerging role of GPCRs in pain. Molecular Interventions. 2009 (9):5; 234-251. The LH/HCG receptor is a GPCR. Id.
The LH/HCG receptor complex specifically has been specifically shown to complex with the Gαi/o group resulting in modulation of neurotransmission. Hu L, Wada k, Mores N, Krsmanovic L Z, Catt K J. Essential role of G protein-gated inwardly rectifying potassium channels in gonadotropin-induced regulation of GnRH neuronal firing and pulsatile neurosecretion. Jour Biol Chem. 2006:281(35); 25231-25240.
Gαi/o proteins mediate the widespread inhibitory effects of many neurotransmitters and they mediate the effects of almost all analgesic GCPR agonists. Stone L S, Molliver D C. In search of analgesia: Emerging role of GPCRs in pain. Molecular Interventions. 2009 (9):5; 234-251.
Due to the multiplicity of pathways involved in establishing central sensitization, chronic pain is a complex phenomenon that can be difficult to treat with single-pathway-active-agent therapy. See Latremoliere A, Woolf C J. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J Pain. 2009 September; 10(9):895-926.
This may explain why there remains a critical dearth of effective medical interventions to treat chronic pain disorders. Traditional pharmaceutical approaches generally deal with a single involved pathway, which tends to yield less than ideal results and is often associated with significant toxicity. For example, the treatment options most commonly investigated to date consist of centrally acting drugs. These include ketamine, dextromethorphan, gabapentin, pregabalin, duloxetine, milnacipran, lamotrigene; and not all of these have reached human trials at this time. Each has demonstrated a poor therapeutic index in trials.
Thus, there is still a need for apparatus, systems, and methods for treating chronic pain, and more generally central sensitization that approaches this disorder in a pleiotropic fashion.